Anti-inflammatory agents, such as corticosteroids, aminosalicylates, azathioprine, metronidazole and cyclosporin, are widely known and used to treat conditions such as inflammatory bowel disease. The use of carbohydrate-derived compounds to treat such conditions is, however, an emerging science.
One of the best-studied examples is that of the tetrasaccharide Sialyl LewisX 1, both as a stand-alone molecule and as part of larger oligosaccharides and glycoproteins.

A review by Lowe in 2002 (Immunological Reviews, 186, (2002), pp. 19-36), for instance, has highlighted the role Sialyl LewisX capped glycoproteins, and in particular 6-O-GlcNAc sulphate-modified derivatives, play in selectin counter-receptor activity by binding to selectins.
Selectins, in particular E-, P- and L-selectins, are proteins responsible for the initial recognition and adhesion of leukocytes to the vascular endothelium. This in turn influences the immune response at sites of chronic inflammation.
The inhibition of E-selectin expression has also been shown to dramatically improve patient survival rates, whilst the expression of Sialyl LewisX and the similar Sialyl LewisA (a trisaccharide lacking the terminal L-fucosyl group of Sialyl LewisX) has been implicated as a marker for metastasis and tumour progression in cancer patients (see the review by J. L. Magnani, Archiv. Biochem. Biophys., 426, (2004), pp. 122-131).
It has also been demonstrated that, in addition to the selectin binding discussed above, 6-O-GlcNAc sulphate-modified Sialyl LewisX derivatives may bind to certain Siglecs (sialic acid recognising, Ig-superfamily lectins), playing a role in, for example, intracellular signalling and cell-cell interactions (see Varki et al, Glycobiology, 16(1), (2006), pp. 1R-27R).
Thus, inhibitory analogues of Sialyl LewisX have become key targets in the search for new classes of drugs. To date, successful inhibitors of selectins derived by this route include the E-selectin inhibitor 2 and the P-selectin inhibitor 3 (see Magnani).

There is still a need, however, for further selectin inhibitors to be developed; sulphated glycosylamines remain unexplored in this respect.
A number of glycosylamines are known to be biologically active, for example, di-β-D-glucosylamine 4 has been shown to inhibit β-glucosidases (Kolarova et al, Carbohydrate Research, 273, (1995), pp. 109-114), although this activity was greatly reduced when N-acetylated.

This compound has also been implicated as an anti-inflammatory agent (see U.S. Pat. No. 5,631,245). When administered to mice by parenteral routes, it inhibits articular inflammation (Bolton et al, Inflamm. Res., Suppl. 2, (2005), p. S121), however it is inactive when given by the oral route, the glycosylamine group being readily hydrolysed under the acid conditions of the stomach. Although the mechanism by which it operates is not clear, it inhibits antigen induced immune cell proliferation and interleukin-2, interleukin-10 and IFN synthesis by antigen stimulated mice spleen cells in vitro. These actions are consistent with an anti-inflammatory and anti-immune profile of activity. In addition, di-β-D-glucosylamine prevents the development of ocular inflammation resulting from the reactivation of feline herpes infection (Roberts et al, XII Annual Meeting of the ACVO, Oct. 11-14, 1990, Scottsdale, Ariz.).
Sulphated carbohydrate derivatives, other than the sulphate-modified Sialyl LewisX derivatives discussed above, have been explored for a wide variety of reasons. For instance, there is a class of sulphated glycosaminoglycan binding proteins, which perform a vast array of functions and are capable of recognising, for example, the subgroups of the naturally occurring heparan sulphate, dermatan sulphate or chondroitin sulphate (with repeating subgroup 5) glycosaminoglycans. Chondroitin sulphate reduces inflammatory cell accumulation and inflammation in inflamed joints (Ronca et al, Osteoarthritis and Cartilage, 6(Suppl. A), (1998), pp. 14-21).

At the other end of the spectrum, a number of sulphated mono- and di-saccharides are well known and possess a range of biological activities. Perhaps the most extensively studied of these (primarily due to its low cost) is sucrose octasulphate. U.S. Pat. No. 5,202,311 for instance discloses the use of sucrose octasulphate and its aluminium/sodium salts for the stabilisation of fibroblast growth factor (FGF) and the use of the resultant composition to treat gastrointestinal ulcerations and other diseases responsive to FGF therapy. This stabilisation and resultant signalling has been hypothesised to be the result of sucrose octasulphate induced FGF dependent dimerisation of FGF receptors via the formation of a ternary complex in which sucrose octasulphate binds to both FGF and FGF receptors (Yeh et al, Mol. Cell. Biology, 22(20), (2002), pp. 7184-7192). Interestingly, the same study noted that the dimerisation occurred to a much lesser extent or not at all with 2-hydroxysucrose heptasulphate and 4,6-dihydroxysucrose hexasulphate respectively.
However, the enhancement of such FGF activity by sulphated carbohydrates is unlikely to result in anti-inflammatory activity, indeed FGF itself does not induce cell inflammatory cell recruitment, but when given with inflammatory cytokines such as tumour necrosis factor interferon, C5a or delayed-type hypersensitivity, it enhances inflammation (Zittermann et al, American Journal of Pathology, 168(3), (2006), pp. 835-846). In addition, FGF is intimately involved in the process of angiogenesis (Presta et al, Cytokine and Growth Factor Reviews, 16, (2005), pp. 159-178), and this is enhanced by heparinoid compounds. Angiogenesis is required for the development of chronic inflammatory tissues, but is also required for wound healing.
Sucrose octasulphate has also been shown to bind to the C-type lectin-like domain of a recombinant natural killer cell receptor (Kogelberg et al, Chem. Bio. Chem., 3, (2002), pp. 1072-1077), to a hepatocyte growth factor (Zhou et al, Biochemistry, 38(45), (1999), pp. 14793-14802), to follistatin (Innis et al, J. Biol. Chem., 278(41), (2003), pp. 39969-39977), and the pro-inflammatory chemokine MCP-1 (Yonghao et al, J. Am. Soc. Mass Spectrometry, 17, (2006), pp. 524-535; Yonghao et al, J. Biol. Chem., 280(37), (2005), pp. 32200-32208).
Sulphated oligosaccharides reduce inflammatory cell rolling and accumulation through the interference with P- and L-selectins (Walsh et al, Clinical Science, 81(3), (1991), pp. 341-346), and heparin-derived disaccharides purified from porcine blood inhibit murine macrophage tumour necrosis factor synthesis and inflammation (Cahalon et al, Int. Immunol., 9(10), (1997), pp. 1517-1522). Such sulphated disaccharides can bind chemokines that are involved in cell recruitment (Shaw et al, Structure, 12, (2004), pp. 2081-2089).
The biological activity of sucrose octasulphate has largely been explained to be a result of its ability to mimic the binding of the glycosaminoglycans heparan sulphate and heparin sulphate. Notably, however, studies on the isolated disaccharide 4-deoxy-α-L-threo-hex-4-ene-pyranosyluronic acid (1-4)-2-amino-2-deoxy-2,6-di-O-sulpho-glucopyranose, which is repeatedly present in heparin, have not always shown the same binding ability (see Kogelberg et al).
Also of note is the fact that sulphated glycosaminoglycans are desulphated to their constituent carbohydrates by vascular endothelium, and inactivated (Dawes & Pepper, Thrombosis and Haemostasis, 67(4), (1992), pp. 468-472). Indeed, desulphated heparin disaccharide O-(α-L-ido-4-enepyranosyluronic acid)-(1→4)-2-deoxy-N-acetyl-D-glucoseamine is ineffective as an anti-inflammatory agent (Cahalon et al, Int. Immunol., 9(10), (1997), pp. 1517-1522), unlike di-β-D-glucosylamine which possesses inherent anti-inflammatory activity (see Bolton et al).
Sulphated monosaccharides are known to occur in nature. One such monosaccharide is 3′-phosphoadenosine-5′-phosphosulphate (PAPS), 6.

PAPS is active throughout the mammalian metabolism, where it has been identified as an activated sulphate molecule which represents the universal sulphonate donor for all sulphotransferase reactions. It therefore performs an essential role within the body, acting for instance to sulphonate the glycosaminoglycans referred to above, or to sulphonate xenobiotics in order to make them more hydrophilic and thereby encourage their excretion from the body (Venkatachalam et al, J. Biol. Chem., 273(30), (1998), pp. 19311-19320).